1. Field of the Invention
This invention relates to methods and compositions for treating proliferative disorders, such as cancers, blood vessel disorders and fibrotic disorders, using N-(3-methyl-4-trifluoromethylphenyl) 2-cyano-2-(cycloalkylcarbonyl)acetamide compounds or pharmaceutical compositions comprising such compounds.
2. References
The following publications, patents and patent applications are cited in this application as superscript numbers:
1 U.S. Pat. No. 4,284,786, issued Aug. 18, 1981, to Kammerer et al.
2 U.S. Pat. No. 4,351,841, issued Sep. 28, 1982, to Kammerer et al.
3 U.S. Pat. No. 5,700,822, issued Dec. 23, 1997, to Hirth et al.
4 U.S. Pat. No. 5,700,823, issued Dec. 23, 1997, to Hirth et al.
5 U.S. Pat. No. 5,721,277, issued Feb. 24, 1998, to Tang.
6 International Publication No. WO 95/19169, published Jul. 20, 1995.
7 U.S. Pat. No. 5,240,960, issued Aug. 31, 1993, to Hambleton et al.
8 U.S. Pat. No. 5,384,423, issued Jan. 24, 1995, to Hambleton et al.
Each of the publications, patents and patent applications referred to in this application, including those listed above, are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
Proliferative growth of cells, tissues and organs occurs in various mammalian disorders, such as cancers, blood vessel disorders and fibrotic disorders. The compounds leflunomide (also known as 5-methylisoxazole-4-carboxylic acid-(4-trifluromethyl)-anilide) and N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide have been reported to be useful in inhibiting hyper-proliferative cell growth. Leflunomide reportedly acts as a pro-drug for the in vivo formation of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide. See, for example, U.S. Pat. No. 4,284,7861 and U.S. Pat. No. 4,351,841.2 Other compounds reportedly useful for the treatment of cell proliferation disorders are disclosed in U.S. Pat. No. 5,700,822;3 U.S. Pat. No. 5,700,823;4 U.S. Pat. No. 5,721,277;5 and International Publication No. WO 95/19169.6 
U.S. Pat. No. 5,240,9607 and U.S. Pat. No. 5,384,4238 disclose various N-(substituted phenyl) 2-cyano-2-(cycloalkylcarbonyl)acetamide compounds and methods for treating inflammation in warm-blooded animals using such compounds.
Surprisingly, it has now been discovered that certain N-(substituted phenyl) 2-cyano-2-(cycloalkylcarbonyl)acetamide compounds, i.e., those having a 3-methyl-4-trifluoromethylphenyl group, are also useful for the treatment of proliferative disorders, such as cancers, blood vessel disorders, fibrotic disorders and the rejection of transplanted organs, tissues and cells.
The present invention is directed to methods and compositions for treating proliferative disorders using N-(3-methyl-4-trifluoromethylphenyl) 2-cyano-2-(cycloalkylcarbonyl)acetamide compounds or pharmaceutical compositions comprising such compounds.
Accordingly, in one of its method aspects, the present invention provides a method of treating a cell, tissue or organ with a proliferative disorder comprising administering to said cell, tissue or organ a proliferation-inhibiting amount of a compound of formula I or a tautomeric isomer thereof: 
wherein
R1 is hydrogen or alkyl of from 1 to 3 carbon atoms;
R2 is cycloalkyl or substituted cycloalkyl having from 3 to 6 carbon atoms in the cycloalkyl ring; or a pharmaceutically-acceptable salt or pro-drug thereof; and
further wherein the proliferation-inhibiting amount provides a concentration of the compound of formula I in the cell, tissue or organ which inhibits the proliferative disorder.
Preferably, in the methods of this invention, R1 in formula I is hydrogen or methyl. More preferably, R1 is hydrogen.
R2 in formula I is preferably cyclopropyl, cyclobutyl or cyclopentyl. More preferably, R2 is cyclopropyl. In a particularly preferred embodiment, R1 is hydrogen and R2 is cyclopropyl.
Preferably, the proliferation-inhibiting amount employed in the above method provides a concentration of the compound of formula I in the cell, tissue or organ from about 0.1 xcexcg/mL to about 1000 xcexcg/mL.
In another of its method aspects, the present invention provides a method of treating a mammal having a proliferative disorder comprising administering to said mammal a proliferation-inhibiting amount of a compound of formula I or a tautomeric isomer thereof: 
wherein
R1 is hydrogen or alkyl of from 1 to 3 carbon atoms; and
R2 is cycloalkyl or substituted cycloalkyl having from 3 to 6 carbon atoms in the cycloalkyl ring; or a pharmaceutically-acceptable salt or pro-drug thereof.
Preferably, the proliferation-inhibiting amount of the compound of formula I ranges from about 0.001 mg/kg/day to about 2000 mg/kg/day; more preferably, from about 0.01 mg/kg/day to about 1000 mg/kg/day, and still more preferably, from about 1 mg/kg/day to about 1000 mg/kg/day.
In a preferred embodiment of the methods of this invention, the proliferative disorder being treated by the compounds of formula I is a cancer; preferably, a solid tumor cancer, a bone marrow cell cancer or lymphatic or lymph node-related cancer; more preferably, a solid tumor cancer, or lymphatic or lymph node-related cancer.
In other preferred embodiments of this invention, the proliferative disorder being treated is a blood vessel proliferative disorder or a fibrotic disorder.
In yet another preferred embodiment of this invention, the proliferative disorder being treated is the acute or chronic rejection of a transplanted organ, tissue or cell.
In the methods of this invention, the compound of formula I is preferably administered orally, intravenously, parenterally or transdermally.
In one embodiment of this invention, the compounds of formula I are administered in a manner to establish an adequate plasma level of the compound of formula I in the mammal being treated. In this embodiment, a compound of formula I is administered to said mammal in a dosing cycle comprising the steps of:
(a) administering to the mammal a first proliferation-inhibiting amount for a period of 1 to 21 days; and then
(b) administering to the mammal a second proliferation-inhibiting amount for a period of 1 to 21 days,
wherein said second proliferation-inhibiting amount is the same or different from said first proliferation-inhibiting amount.
If desired, this dosing cycle can optionally further comprise a non-dosing period of from 1 to 21 days between step(a) and step (b).
Preferably, the ratio of the second proliferation-inhibiting amount to the first proliferation-inhibiting amount ranges from about 1:1 to about 1:6, and if a reduction in ratio below 1:1 is required, then more preferably, from about 2:6 to about 4:6. This treatment regime may be repeated any number of times to establish and/or maintain an adequate plasma level of the compound of formula I in the mammal being treated, i.e., a plurality of such dosing cycles can be administered to the mammal.
The compounds of formula I may be administered to a mammal with a proliferative disorder before, after or in conjunction with other chemotherapeutic agents or with other therapy intended to modulate, to suppress or to stimulate the mammal""s immune system. Additionally, the compounds of formula I can be administered before, in conjunction with, or after other conventional methods for treating proliferative disorders, such as radiation therapy, ablative or partially ablative surgical procedures or a bone marrow transplant, which themselves may be employed in conjunction with chemotherapeutic agents or with other therapy intended to modulate, suppress or stimulate the mammal""s immune system.
When administered with another chemotherapeutic agent or agents, each chemotherapeutic agent is preferably independently selected from the group consisting of androgens, asparaginase, azathioprine, 5-azacitidine, BCG, bleomycin, busulfan, carbetimer, carboplatin chlorambucil, cisplatin, corticosteroids, cyclophosphamide, cytarabine, dacarbazine, dactinomicin, daunomycin, doxorubicin, epirubicin, estrogens, etoposide, fadrazole, 5-flurouracil, gemcitabine, hydroxyurea, ifosfamide, interferon alpha, interferon beta, interferon gamma, an interleukin, isotretinoin, lomustine, melphalan, 6-mercaptopurine, methotrexate, mitomycin-c, mitotane, mitoxantrone, paclitaxel, pentostatin, procabazine, progestins, rituximab, streptozocin, tamoxifen, toxotere, teniposide, thioguanine, thiotepa, topotecan, toremifene, tretinoin, uracil mustard, vinblastine, vincristine and vinorelbine; or other drugs intended to affect or alter, directly or indirectly, the replication or functioning of cellular deoxyribonucleic acid or cellular ribonucleic acid, or other drugs intended to affect or alter, directly or indirectly, the functioning of the immune system.
When the proliferative disorder being treated is acute or chronic rejection of a transplanted organ, tissue or cell, the compound of formula I may be administered in combination with one or more immunosuppressive agents. Preferably, each immunosuppressive agent is independently selected from the group consisting of azathioprine, corticosteroids, cyclosporin, cyclophosphamide, mycophenolic acid or congeners thereof, monoclonal or polyclonal antibodies, or other agents or procedures used to prevent, suppress or reverse rejection of a transplanted organ, tissue or cell.
Accordingly, in one of its composition aspects, this invention provides a pharmaceutical composition or admixture comprising:
(a) about 1 to about 99 weight percent of a first composition comprising a compound of formula I or a tautomeric isomer thereof: 
xe2x80x83wherein
R1 is hydrogen or alkyl of from 1 to 3 carbon atoms; and
R2 is cycloalkyl or substituted cycloalkyl having from 3 to 6 carbon atoms in the cycloalkyl ring; or a pharmaceutically-acceptable salt or pro-drug thereof;
(b) about 1 to about 99 weight percent of a second composition comprising one or more chemotherapeutic agents, or one or more immunosuppressive agents; and
(c) from 0 to about 98 weight percent of a pharmaceutically-acceptable carrier.
Among other properties, the compounds of formula I have been discovered to be particularly useful for treating solid tumors. Accordingly, in a particularly preferred embodiment, the present invention provides a method of inhibiting tumor growth in a mammal having a solid tumor comprising administering to said mammal a tumor growth-inhibiting amount of a compound of formula II or a tautomeric isomer thereof: 
or a pharmaceutically-acceptable salt or pro-drug thereof.
This invention provides methods of treating proliferative disorders using N-(3-methyl-4-trifluoromethylphenyl) 2-cyano-2-(cycloalkylcarbonyl)-acetamide compounds and pharmaceutical compositions comprising such compounds. When describing the methods, compositions and compounds of this invention, the following terms have the following meanings unless otherwise indicated. Those terms not defined have their art-recognized meanings.
xe2x80x9cAcylxe2x80x9d refers to the group xe2x80x94C(O)Ra where Ra is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloakenyl or aryl.
xe2x80x9cAcylaminoxe2x80x9d refers to the group xe2x80x94NRaC(O)Ra where Ra is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloakenyl or aryl.
xe2x80x9cAcyloxyxe2x80x9d refers to the group xe2x80x94OC(O)Ra where Ra is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitued alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloakenyl or aryl.
xe2x80x9cAlkenylxe2x80x9d refers to monovalent branched or unbranched hydrocarbon groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. Representative alkenyl groups include ethenyl (xe2x80x94CHxe2x95x90CH2), n-propenyl (xe2x80x94CH2CHxe2x95x90CH2), isopropenyl (xe2x80x94C(CH3)xe2x95x90CH2) and the like.
xe2x80x9cSubstituted alkenylxe2x80x9d refers to an alkenyl group having 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, aryloxycarbonyl, aryloxycarbonylamino, carboxyl, cyano, cycloalkyl, cycloalkenyl, halogen, hydroxy, nitro, oxo, sulfo, sulfonamide, thiol, thioalkoxy, thioaryloxy, thiooxo, trifluoromethyl, trifluoromethoxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl and xe2x80x94SO2-aryl.
xe2x80x9cAlkoxyxe2x80x9d refers to the group xe2x80x94ORb where Rb is alkyl or substituted alkyl. Representative alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d refers to the group xe2x80x94C(O)ORc where Rc is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl.
xe2x80x9cAlkoxycarbonylaminoxe2x80x9d refers to the group xe2x80x94NRaC(O)ORc where Ra is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloakenyl or aryl; and Rc is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl.
xe2x80x9cAlkylxe2x80x9d refers to monovalent branched or unbranched hydrocarbon groups preferably having from 1 to about 10 carbon atoms, more preferably 1 to 8 carbon atoms and still more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, lert-butyl, n-hexyl, n-octyl and the like. The term xe2x80x9clower alkylxe2x80x9d refers to alkyl groups having 1 to 6 carbon atoms.
xe2x80x9cSubstituted alkylxe2x80x9d refers to an alkyl group having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, aryloxycarbonyl, aryloxycarbonylamino, carboxyl, cyano, cycloalkyl, cycloalkenyl, halogen, hydroxy, nitro, oxo, sulfo, sulfonamide, thiol, thioalkoxy, thioaryloxy, thiooxo, trifluoromethyl, trifluoromethoxy, xe2x80x94SOxe2x80x94Rc and xe2x80x94SO2xe2x80x94Rc, where Rc is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl.
xe2x80x9cAlkynylxe2x80x9d refers to monovalent branched or unbranched hydrocarbon groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation. Representative alkynyl groups include ethynyl (xe2x80x94Cxe2x89xa1CH), propargyl (xe2x80x94CH2Cxe2x89xa1CH), and the like.
xe2x80x9cSubstituted alkynylxe2x80x9d refers to an alkynyl group having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, aryloxycarbonyl, aryloxycarbonylamino, carboxyl, cyano, cycloalkyl, cycloalkenyl, halogen, hydroxy, nitro, oxo, sulfo, sulfonamide, thiol, thioalkoxy, thioaryloxy, thiooxo, trifluoromethyl, trifluoromethoxy, xe2x80x94SOxe2x80x94Rc and xe2x80x94SO2xe2x80x94Rc, where Rc is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl.
xe2x80x9cAminoxe2x80x9d refers to the group xe2x80x94NH2.
xe2x80x9cSubstituted aminoxe2x80x9d refers to the group xe2x80x94NRaRa where each Ra is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloakenyl or aryl, provide both of Ra are not hydrogen.
xe2x80x9cAminocarbonylxe2x80x9d refers to the group xe2x80x94C(O)NRaRa where each Ra is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloakenyl or aryl.
xe2x80x9cAminocarbonylaminoxe2x80x9d refers to the group xe2x80x94NRaC(O)NRaRa where each Ra is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloakenyl or aryl.
xe2x80x9cAminocarbonyloxyxe2x80x9d refers to the group xe2x80x94OC(O)NRaRa where each Ra is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloakenyl or aryl.
xe2x80x9cArylxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like. Unless otherwise constrained by the definition for the individual substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, aryloxycarbonyl, aryloxycarbonylamino, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, halogen, hydroxy, nitro, sulfo, sulfonamide, thiol, thioalkoxy, thioaryloxy, trifluoromethyl, trifluoromethoxy, xe2x80x94SOxe2x80x94Rc and xe2x80x94SO2xe2x80x94Rc, where Rc is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl.
xe2x80x9cAryloxyxe2x80x9d refers to xe2x80x94ORd wherein Rd is aryl.
xe2x80x9cAryloxycarbonylxe2x80x9d refers to xe2x80x94C(O)ORd wherein Rd is aryl.
xe2x80x9cAryloxycarbonylaminoxe2x80x9d refers to xe2x80x94NRaC(O)ORc where Ra is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloakenyl or aryl, and Rd is aryl.
xe2x80x9cCarboxylxe2x80x9d refers to the group xe2x80x94C(O)OH.
xe2x80x9cCyanoxe2x80x9d refers to the group xe2x80x94CN.
xe2x80x9cCycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems, which can be optionally substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
xe2x80x9cSubstituted cycloalkylxe2x80x9d refers to a cycloalkyl group having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, aryloxycarbonyl, aryloxycarbonylamino, carboxyl, cyano, cycloalkyl, cycloalkenyl, halogen, hydroxy, nitro, oxo, sulfo, sulfonamide, thiol, thioalkoxy, thioaryloxy, thiooxo, trifluoromethyl, trifluoromethoxy, xe2x80x94SOxe2x80x94Rc and xe2x80x94SO2xe2x80x94Rc, where Rc is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl.
xe2x80x9cCycloalkenylxe2x80x9d refers to cyclic alkenyl groups of from 4 to 10 carbon atoms having a single cyclic ring and at least one point of internal unsaturation which can be optionally substituted with from 1 to 3 alkyl groups. Examples of suitable cycloalkenyl groups include, for instance, cyclopent-3-enyl, cyclohex-2-enyl, cyclooct-3-enyl and the like.
xe2x80x9cSubstituted cycloalkenylxe2x80x9d refers to a cycloalkenyl group having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, aryloxycarbonyl, aryloxycarbonylamino, carboxyl, cyano, cycloalkyl, cycloalkenyl, halogen, hydroxy, nitro, oxo, sulfo, sulfonamide, thiol, thioalkoxy, thioaryloxy, thiooxo, trifluoromethyl, trifluoromethoxy, xe2x80x94SOxe2x80x94Rc and xe2x80x94SO2xe2x80x94Rc, where Rc is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo. Preferred halo groups are either fluoro or chloro.
xe2x80x9cHydroxyxe2x80x9d refers to the group xe2x80x94OH.
xe2x80x9cKetoxe2x80x9d or xe2x80x9coxoxe2x80x9d refers to the group xe2x95x90O.
xe2x80x9cNitroxe2x80x9d refers to the group xe2x80x94NO2.
xe2x80x9cSulfoxe2x80x9d refers to the group xe2x80x94SO3H.
xe2x80x9cSulfonamidexe2x80x9d refers to the group xe2x80x94SO2NRaRa where each Ra is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloakenyl or aryl.
xe2x80x9cThiolxe2x80x9d refers to the group xe2x80x94SH.
xe2x80x9cThioalkoxyxe2x80x9d refers to the group xe2x80x94SRb where Rb is alkyl or substituted alkyl.
xe2x80x9cThioaryloxyxe2x80x9d refers to the group xe2x80x94SRd where Rd is aryl.
xe2x80x9cThioketoxe2x80x9d or xe2x80x9cthioxoxe2x80x9d refers to the group xe2x95x90S.
xe2x80x9cTrifluoromethoxyxe2x80x9d refers to the group xe2x80x94OCF3.
xe2x80x9cTrifluoromethylxe2x80x9d refers to the group xe2x80x94CF3.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
xe2x80x9cPro-drugsxe2x80x9d means any compound which releases a biologically active compound of formula I in vivo when such a pro-drug is administered to a mammalian subject. Pro-drugs of a compound of formula I are prepared by modifying functional groups present in the compound of formula I in such a way that the modifications may be cleaved in vivo to release the parent compound. Pro-drugs include, by way of illustration, compounds wherein a hydroxy, amino, carboxyl, or thiol group is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, carboxyl, or thiol group, respectively. Examples of pro-drugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), amides and the like.
The term xe2x80x9ctautomersxe2x80x9d or xe2x80x9ctautomeric isomersxe2x80x9d refers to two of more isomers of a keto compound, i.e. a compound of formula I, which differ only by placement of a proton and the corresponding location of the double bond, i.e., the keto and enol forms of a keto compound. Typically, an equilibrium exists, particularly in solution, between the keto and enol forms of such compounds. For example, the compound of formula II (Laflunimus) can be either in its keto or enol form as shown below: 
When referring to one form of the compound the other is inclusive of that form. Additionally, it will readily apparent to a person skilled in the art that the relative ratios of the two forms will depend on the environment around the compound such as pH, and the like.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9cTreatmentxe2x80x9d of a Disease Includes:
(1) preventing the disease, i.e. causing the clinical symptoms or signs of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but which does not yet experience or display symptoms or signs of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the rate of development of the disease or its clinical symptoms or signs,
(3) relieving the disease, i.e., causing partial or complete regression of the disease or its clinical symptoms or signs,
(4) a combination of (1), (2) or (3) above encompassing different clinical symptoms or signs.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal to treat a disease, is sufficient to effect treatment of the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d may vary depending on the compound, the disease and its status or severity, the age, weight, other medical conditions, etc., of the mammal to be treated. A xe2x80x9cproliferation-inhibiting amountxe2x80x9d means an amount of a compound that is sufficient to effect treatment of a proliferative disorder. The therapeutically effective amount may also vary depending upon one or more past or concurrent medical, surgical, or radiation therapy interventions.
The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, N.Y., 1991, and references cited therein.
Furthermore, the compounds of this invention may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures, or as a racemic mixture. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. Any and all geometric isomers of the compounds of this invention are also included within the scope of this invention including, for example, cis and trans or E- and Z-isomers.
The compounds of formula I can be prepared using the procedures described, for example, in U.S. Pat. No. 5,240,960, issued Aug. 31, 1993, and U.S. Pat. No. 5,384,423, issued Jan. 24, 1995, the disclosures of which are incorporated herein by reference in their entirety. Specifically, the compounds of formula I may be prepared by reacting a compound of formula III: 
where R1 is as defined herein, with a compound of formula IV: 
or an acid derivative thereof to form a compound of formula V: 
Intermediate V is then reacted with a strong base, such as sodium hydride, optionally in the presence of a catalyst such as imidazole, to form the corresponding anion which is then reacted with a compound of formula VI:
R2COHalxe2x80x83xe2x80x83VI
where R2 is as defined herein and Hal is a halogen, to provide the compound of formula I.
Compounds of formula III are either commercially available or may be prepared using conventional reagent and procedures from commercially available starting materials. Preferred compounds of formula III include, by way of illustration, 3-methyl-4-trifluoromethylaniline, N-methyl-3-methyl-4-trifluoromethylaniline, N-ethyl-3-methyl-4-trifluoromethylaniline and the like.
Similarly, compounds of formula IV and VI are either commercially available or may be prepared using conventional reagent and procedures from commercially available starting materials. For example, cyanoacetic acid, IV, is commercially available from Aldrich Chemical Company, Milwaukee, Wis. 53201 USA. Preferred compounds of formula VI include, by way of example, cyclopropanecarbonyl chloride (e.g., Aldrich), 2,2,3,3-tetramethylcyclopropane-1-carbonyl chloride, cyclobutanecarbonyl chloride (e.g., Aldrich), cyclopentanecarbonyl chloride (e.g., Aldrich), cyclohexanecarbonyl chloride (e.g., Aldrich) and the like.
Preferably, the reaction of the compounds of formulae III and IV is conducted in the presence of diisopropylcarbodiimide or dichlorohexyl-carbodiimide in an anhydrous organic solvent, such as dichloromethane or tetrahydrofuran. A preferred functional derivative of the acid of formula IV is cyanoacetyl chloride prepared in situ from phosphorus pentachloride and cyanoacetic acid.
The reaction of the compound of formula V with sodium hydride is preferably conducted in an anhydrous organic solvent such as tetrahydrofuran. The reaction of the resulting anion of V with a compound of formula VI is preferably conducted in an anhydrous organic solvent such as dichloromethane.
The compounds of formula I have an acidic character and the addition salts of such compounds may be prepared by reacting approximately stoichiometric amounts of a compound of formula I with a base with or without prior isolation of the compound of formula 1.
When employed in the methods of this invention, the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
The pharmaceutical compositions employed in the methods of this invention contain, as the active ingredient, one or more of the compounds of formula I associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of, e.g., less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg, more usually about 25 to about 500 mg, and most commonly from about 100 to about 200 mg of the active ingredient. The term xe2x80x9cunit dosage formsxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient""s symptoms, signs, prior or concurrent medical, surgical, or radiation therapy, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.